US11957791B2 - Methods - Google Patents

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US11957791B2
US11957791B2 US17/270,573 US201917270573A US11957791B2 US 11957791 B2 US11957791 B2 US 11957791B2 US 201917270573 A US201917270573 A US 201917270573A US 11957791 B2 US11957791 B2 US 11957791B2
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dosage form
lumateperone
tosylate
cellulose
weight
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US20210220280A1 (en
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Peng Li
Robert Davis
William Paul FINDLAY
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Intra Cellular Therapies Inc
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Intra Cellular Therapies Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to solid oral dosage forms comprising lumateperone, in free, or pharmaceutically acceptable salt form, optionally in combination with one or more additional therapeutic agents, processes for manufacture thereof and methods of use in the treatment or prophylaxis of disease.
  • the substituted heterocycle fused gamma-carbolines lumateperone (4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone) is known to be a serotonin receptor (5-HT2A), dopamine receptor (D1 and/or D2), and serotonin transporter (SERT) ligand, which is useful in treating a variety of central nervous system disorders.
  • 5-HT2A serotonin receptor
  • D1 and/or D2 dopamine receptor
  • SERT serotonin transporter
  • Lumateperone antagonizes the serotonin-2A (5-HT2A) receptor, and/or modulates dopamine receptor signaling at the level of key intra-cellular phosphoproteins.
  • This compound is principally known to be useful for the treatment of positive and negative symptoms of schizophrenia, depression (especially acute depression and bipolar depression), anxiety and traumatic disorders (including acute anxiety and post-traumatic stress disorder), and dementias (including Alzheimer's disease and the symptoms associated therewith).
  • this compound has dual properties and acts as both a post-synaptic antagonist and a pre-synaptic partial agonist of the D2 receptor.
  • the compound also stimulates phosphorylation of glutamatergic NMDA NR2B, or GluN2B, receptors in a mesolimbic specific manner. It is believed that this regional selectivity in the brain areas thought to mediate the efficacy of antipsychotic drugs, together with the serotonergic, glutamatergic, and dopaminergic interactions, may result in antipsychotic efficacy for positive, negative, affective and cognitive symptoms associated with schizophrenia.
  • the compound also exhibits serotonin reuptake inhibition, providing antidepressant activity for the treatment of schizoaffective disorder, co-morbid depression, and/or as a stand-alone treatment for major depressive disorder.
  • Lumateperone is also useful for the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disturbances associated with dementia, autism and other CNS diseases. These features may be able to improve the quality of life of patients with schizophrenia and enhance social function to allow them to more fully integrate into their families and their workplace. Lumateperone displays differential dose-dependent effects, selectively targeting the 5-HT2A receptor at low doses, while progressively interacting with the D2 receptor at higher doses. As a result, at lower doses, it is useful in treating sleep, aggression and agitation. At a high dose, it can treat acute exacerbated and residual schizophrenia, bipolar disorders, and mood disorders.
  • Lumateperone having the formula:
  • Lumateperone is in Phase III clinical development as a treatment for schizophrenia, bipolar depression and agitation in dementia, including Alzheimer's Disease.
  • Lumateperone and related compounds have been disclosed in U.S. Pat. Nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, U.S. RE39680, and U.S. RE39679 (each of which are incorporated herein by reference) as novel compounds useful for the treatment of disorders associated with 5-HT2A receptor modulation such as anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, and social phobias.
  • disorders associated with 5-HT2A receptor modulation such as anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, and social phobias.
  • 7,081,455 also disclose methods of making substituted heterocycle fused gamma-carbolines and uses of these gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders.
  • WO 2011/133224 and U.S. Pat. No. 8,993,572 each incorporated herein by reference, disclose prodrugs/metabolites of substituted heterocycle fused gamma-carboline for improved formulation, e.g., extended/controlled release formulation.
  • This application discloses that heterocycle fused gamma-carboline N-substituted with a 4-fluorophenyl(4-hydroxy)butyl moiety are shown to have high selectivity for the serotonin transporter (SERT) relative to the heterocycle fused gamma-carboline containing 4-fluorophenylbutanone.
  • SERT serotonin transporter
  • WO 2009/145900 (and U.S. Pat. No. 8,598,119, incorporated herein by reference) teaches that selected substituted heterocycle fused gamma-carboline compounds have nanomolar affinity for the serotonin reuptake transporter (SERT) and so are selective serotonin reuptake inhibitors.
  • SERT serotonin reuptake transporter
  • Lumateperone may be particularly effective in treating acute depression and acute anxiety owing to its rapid onset of action compared to existing antidepressants, as disclosed in PCT/US2019/035845 (incorporated herein by reference in its entirety). This is believed to be due to its signaling through a neurotransmitter system separate from the traditional monoamine signaling systems.
  • Lumateperone provides a dopamine D1 receptor-dependent enhancement of NMDA and AMPA currents coupled with activation of the mTOR (e.g., mTORC1) signaling pathway.
  • the present disclosure provides solid oral dosage forms comprising lumateperone in free or pharmaceutically acceptable salt form.
  • the dosage form is a tablet.
  • the dosage form further comprises one or more additional therapeutic agents. These dosage forms are useful for the treatment or prophylaxis of a variety of central nervous system disorders.
  • Lumateperone is in Phase III clinical development as a treatment for schizophrenia, bipolar depression and agitation in dementia, including Alzheimer's Disease.
  • the present disclosure provides a solid oral dosage form (Dosage Form 1), comprising lumateperone:
  • Dosage Form 1 may be as follows:
  • binders may include one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, polyvinyl pyrrolidone, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like.
  • Each solid dosage form may comprise from 0.5-10% by weight, e.g., 1-5%, or 1-3% by weight each binder.
  • Carmellose calcium, croscarmellose sodium, sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose, powdered agar and the like are used as the disintegrant.
  • the disintegrants such as sodium starch glycolate, croscarmellose sodium and low substituted hydroxypropyl cellulose are preferable.
  • Each tablet can contain 0.1-15% by weight, preferably 1-5% by weight of the disintegrant.
  • the solid dosage form of the present disclosure further comprises an appropriate amount of a flavor, a lubricant, a coloring agent and the like, or various additives which are commonly used for preparing a galenic formulation.
  • Lubricants may include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate and the like.
  • Coloring agents may include the food colors such as food yellow no. 5, food red no. 2, food blue no. 2, food lake colors, iron sesquioxide and the like.
  • a coating mixture may be applied to the solid dosage form by using a well-known method with the purpose of, for example, further masking of a taste and an odor, and preparation of an enteric formulation or a sustained-release formulation after coating a particle core with the active ingredient, one or more additives and the like.
  • Coating mixtures may comprise any suitable water-soluble or water-swellable polymers, such as polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, and polyacrylic acid, for example.
  • the solid dosage forms of the present disclosure include, for example, tablets, caplets, and pills. They do not include capsules or the granules used in capsules.
  • a tablet may have a variety of shapes, including but not limited to, round, oval, square, rectangular, and oblong. Tablets and caplets may optionally be scored for easier cutting. Tablets and caplets may be coated with one, two, three or more layers designed for different purposes (e.g., taste-masking, enteric protection, delayed or sustained release, improve swallowing).
  • the solid dosage forms of the present disclosure may further include any one or more of pharmaceutically acceptable solvents, surface tension modifiers (e.g., surfactants), preservatives, antioxidants, colorants, taste masking agents, flavors and sweeteners.
  • solvents include water and other solvents, which are miscible with water or solubilizing agents and suitable for oral purposes.
  • suitable solvents are ethanol, propylene glycol, glycerol, polyethylene glycols, poloxamers, sorbitol and benzyl alcohol.
  • the aqueous solubility of the lumateperone may further be enhanced by the addition to the solution of a pharmaceutically acceptable co-solvent, a cyclodextrin or a derivative thereof (e.g., dextrans).
  • a pharmaceutically acceptable co-solvent e.g., a cyclodextrin or a derivative thereof (e.g., dextrans).
  • Preservative agents may be added to prevent the growth of microorganisms such as bacteria, yeasts and fungi in liquid formulations, which are likely to be used repeatedly. Suitable preservatives should be physicochemical stable and effective in the desired pH range. Examples of preservative agents include ethanol, methylparaben, propylparaben and benzyl alcohol.
  • the solid dosage forms of the present disclosure include one or more anti-oxidants to guard against degradation of the active.
  • antioxidants include propyl gallate, ascorbyl palmitate, ascorbic acid, t-butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherols, tocotrienols, sodium sulfite, sodium metabisulfite, beta-carotene, citric acid and EDTA.
  • coloring agents may be used to introduce a uniformity of appearance to the product and/or to protect any light-sensitive ingredients.
  • Suitable coloring agents include all dyes and lakes approved by the U.S. Food and Drug Administration (e.g., FD&C colorants).
  • sweetening agents may be used to mask unpleasant taste or to achieve a desired taste.
  • sweetening agents are glucose, sorbitol, glycerol, acesulfame potassium and neohesperidin dihydrochalcon.
  • the taste may be optimized further by the addition of one or more flavoring substances. Suitable flavoring substances are fruit flavors such as cherry, raspberry, black currant, lemon or strawberry flavor or other flavors such as liquorice, anise, peppermint, and caramel.
  • the solid dosage forms of the present disclosure may be prepared by, for example, wet granulating lumateperone, in free or pharmaceutically acceptable salt form, and one or more pharmaceutically acceptable carriers or diluents (i.e., excipients), for example, a binder and/or a disintegrant with water or a binder solution, using a machine such as a high speed mixer granulator, a fluidized-bed granulator dryer, a centrifugal tumbling fluidized-bed granulator coating machine or a kneading machine; blending or spraying a lubricant to the granules; and then subjecting to compression molding.
  • a machine such as a high speed mixer granulator, a fluidized-bed granulator dryer, a centrifugal tumbling fluidized-bed granulator coating machine or a kneading machine
  • the solid dosage forms of the present disclosure can be prepared by dry granulating lumateperone, in free or pharmaceutically acceptable salt form, and one or more pharmaceutically acceptable carriers or diluents (i.e., excipients), for example, a binder (a disintegrant may be further contained), using a machine such as a roller compactor; blending or spraying a disintegrant (a lubricant may be further contained) to the granules; and then subjecting to compression molding.
  • a binder a disintegrant may be further contained
  • a machine such as a roller compactor
  • blending or spraying a disintegrant a lubricant may be further contained
  • Suitable forms of lumateperone include the free base form, including amorphous solid dispersions thereof, pharmaceutically acceptable salt forms, including amorphous solid dispersions and crystal forms thereof, and pharmaceutically acceptable co-crystal forms.
  • Amorphous solid dispersion forms of lumateperone free base are disclosed in patent publication WO 2018/71233, and related applications thereto, the contents of which are hereby incorporated by reference in their entireties.
  • the term “pharmaceutically acceptable salt” includes acid addition salts between lumateperone and any pharmaceutically acceptable acid (e.g., Bronsted acid) in any molar ratio permitted by the structure of the acid.
  • “pharmaceutically acceptable salt form” of lumateperone includes the mono-hydrochloride, the di-hydrochloride, the tri-hydrochloride, the mono-tosylate, the di-tosylate and the tri-tosylate, or any mixtures thereof.
  • the lumateperone salt is a crystalline solid (e.g., a salt crystal).
  • the lumateperone may exist as a co-crystal, i.e., lumateperone free base co-crystallized with a second species.
  • Pharmaceutically acceptable salt and co-crystal forms of lumateperone include all those forms disclosed in U.S. Pat. Nos. 8,648,077, 9,199,995, and 9,586,960, and patent publications WO 2017/1172811 and WO 2017/172784, and U.S. provisional applications 62/563,341 and 62/681,534, the contents of each of which are hereby incorporated by reference in their entireties.
  • the present disclosure provides a process (Process 1) for the manufacture of Dosage Form 1, or any of 1.1-1.49, wherein the process comprises the steps of:
  • lumateperone is provided in the form of an amorphous solid dispersion (either of lumateperone free base or lumateperone tosylate), that in step (a) of Process 1 it is the dispersion that is combined with at least one further diluent or carrier.
  • the amorphous solid dispersion would be prepared in a step antecedent to step (a) by combining the lumateperone and any excipients necessary to form the solid dispersion thereof.
  • steps (d), (e), and/or (f) may be repeated for additional diluents or carriers.
  • the process steps may comprise steps (a), (b), (c), (d1), (e1), (f1), (d2), (e2), (f2), (g), and (h).
  • the steps (d), (e), and (f) may be repeated any number of times to provide for the additional addition, blending/milling and/or filtering of any individual ingredients or portions of ingredients in order to optimize process flow.
  • the binder components may be added in two or three portions, such as in steps (a), (d1) and (d2), or the lubricant may be added in a final addition step (e.g., step (d2)).
  • the process optionally further includes one or more dry granulation steps (e.g., roller compaction or slugging) which serve to increase the size of solid particles from powder-scale to granule-scale.
  • one or more blending steps may further include running the blend through a roller compactor, and optionally then milling the roller compacter ribbons.
  • any dry granulation step may be followed by a blending step to blend the resulting granules with one or more other excipients (e.g., lubricant).
  • the final step of coating the Dosage Form is performed by suspending the un-coated Dosage Form in an aqueous suspension of coating polymer followed by drying to remove the water and any co-solvents.
  • the coating is applied at high temperature and/or the coated tablets are dried at high temperature (e.g., 40 to 60° C.).
  • the coating is applied by spraying an aqueous suspension of the coating polymer onto uncoated Dosage Form, followed by drying.
  • the present disclosure provides a method (Method 1) for the treatment or prophylaxis of a disease or disorder involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, comprising administering to a patient in need thereof the solid dosage form according to Dosage Form 1 or any of 1.1-1.49.
  • Method 1 for the treatment or prophylaxis of a disease or disorder involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, comprising administering to a patient in need thereof the solid dosage form according to Dosage Form 1 or any of 1.1-1.49.
  • said disease or disorder is selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD), acute depression, post-traumatic depression), anxiety (including acute anxiety, panic disorders, phobias, social anxiety disorder, or social withdrawal), psychosis (including acute psychosis), schizophrenia (including residual symptoms of schizophrenia, such as positive and/or negative symptoms of schizophrenia), obsessive-compulsive disorder, sexual disorders, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, anger disorders, agitation (including acute agitation), dementia (including Alzheimer's Disease and Parkinson's dementia), gastrointestinal disorders such as dysfunction of gastrointestinal tract motility, and bipolar disorder (e.g., bipolar depression).
  • depression including major depressive disorder (MDD), acute depression, post-traumatic depression
  • anxiety including acute anxiety, panic disorders, phobias, social anxiety disorder, or social withdrawal
  • psychosis including acute psychosis
  • schizophrenia including residual symptoms of schizophrenia, such as positive and/or negative symptoms of schizophrenia
  • treatment and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease and/or treatment of the cause of the disease.
  • the words “treatment” and “treating” refer to prophylaxis or amelioration of symptoms of the disease.
  • patient may include a human or non-human patient.
  • Isolation or purification of the diastereomers of the Compounds of the Invention may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving beds and the like.
  • the pharmaceutically acceptable salts of lumateperone can be synthesized from the parent compound, which contains basic moieties, by reaction with a suitable acid, by conventional chemical methods.
  • a suitable acid by conventional chemical methods.
  • such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • an amount of an active compound for administration refers to or is based on the amount of the compound in free form (i.e., the calculation of the amount is based on the amount of active moiety in free form, not taking into account the weight of the counter ion in the case of a salt).
  • any disclosure of a numerical range, e.g., “up to X” amount is intended to include the upper numerical limit X. Therefore, a disclosure of “up to 60 mg” is intended to include 60 mg.
  • Excipients evaluated are (1) Fillers (silicified microcrystalline cellulose, and lactose monohydrate); (2) Disintegrants (sodium starch glycolate); (3) Binders (pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and copovidone); and (4) Coating Polymers (polyvinyl alcohol-based film coating comprising PVA, titanium dioxide and talc). Lumateperone tosylate is mixed in a 1:1 weight ratio with each excipient and the mixture is evaluated (1) immediately after mixing, (2) after 4, 8 and 12 weeks of aging at 25° C.
  • mannitol, silicon dioxide, BHT, and lumateperone tosylate are combined in a 3-cubic foot V-blender and mixed for 5 minutes at 25 rpm.
  • a first portion of the microcrystalline cellulose is then added, and the mixture is blended for 5 additional minutes.
  • the blended mixture is passed through a Comil brand conical mill with a round impeller using a 1.6 mm aperture screen and milled/screened.
  • a second portion of cellulose is milled and then combined with the milled blend and a third portion of cellulose, and the mixture is blended for 10 minutes at 25 rpm.
  • HPMC and croscarmellose sodium portions are pre-screened through a 20-mesh screen, then added to the blended mixture and the further blended for 5 minutes at 25 rpm. Finally, the magnesium stearate portion is pre-screened through a 30-mesh screen, added to the blended mixture, and the mixture is further blended for 3 minutes at 25 rpm.
  • the common blend for 28 mg and 42 mg tablets is prepared analogously using a 10 cubic foot V-blender, operated at a reduced speed of 20.5 rpm, with similar blending times.
  • blend uniformity and physical properties are evaluated by taking samples from throughout the blender at the time final blending is stopped (10 locations are each sampled for each V-blender). Mean blend uniformity is found to be about 97% for the 14 mg batch and about 96% for the common blend batch over all three runs of each batch. Physical properties, including particle size distribution, bulk density, tapped density, and flow, are found to be highly consistent between the three runs of each batch.
  • tablets are prepared using a commercial tablet press using 0.2000 inch by 0.4758-inch modified capsule embossed B tooling and tapered dies.
  • Target weight for the 14 mg and 28 mg tablets is 250 mg, and for the 42 mg tablets 375 mg. All batches are compressed using force feed frame. Compression parameters and compression yields are evaluated for each batch run, including average tablet weight, hardness, thickness, friability, and disintegration time. All parameters are found to be compliant and consistent between the batch runs.
  • Tablets are then coated using a commercial multi-pan laboratory coating system using a 30-inch pan.
  • Each batch is coated with a target weight of 5 wt % coating, using a commercial, aqueous polyvinyl alcohol coating suspension comprising 20 wt % solids, using two anti-bearding guns equipped with 1.2 mm nozzles.
  • the coating suspension is mixed for 45 minutes in a stainless-steel tank and then allowed to de-aerate for at least 60 minutes prior to use.
  • Target coating parameters are based on the manufacturer's guidelines. The coating process is found to be acceptable.
  • anti-oxidant free, tablet formulations are prepared according to the formulas shown below for 14-mg, 28-mg and 42-mg tablets:
  • 14 mg and 28 mg tablets are each coated with 12.5 mg of PVA coating (5 wt % of core weight), while 42 mg tablets are coated with 18.75 mg of PVA coating (5 wt % of core weight).
  • Tablets are prepared, as shown in the above table, in 14 mg, 28 mg and 42 mg sizes (free base equivalent; corresponding to 20 mg, 40 mg, or 60 mg, respectively, of lumateperone tosylate).
  • the procedure for preparing the tablets is as follows (amounts in parentheses are with reference to the total amount of indicated ingredient in the composition):
  • Tablets prepared according to the above formulas are packaged in blister packs comprising PVC/PE/PCTFE film and 20-micron aluminum foil (peel-push). The packaged tablets are tested for stability using standard procedures. Tested conditions are (1) initial, (2) 50° C./ambient humidity for 1-3 months, (3) 40° C./75% relative humidity for 1-3 months, and (4) 25° C./60% relative humidity for 1 month. Tablets are assayed using reverse-phase HPLC for lumateperone tosylate content, as well as for known impurities. Tablets are also subject to a standard dissolution test (dissolution in 500 mL 0.1N aqueous hydrochloric acid). The results (batch means) are shown in the table below:
  • the lumateperone assay FIGURE is a reflection of the accuracy of the label claim, as it is presented as a percentage of the label amount (e.g., 14-mg, 28-mg or 42-mg) rather than as a percentage of the tablet composition. Acceptance of a batch requires that the batch of tablets is measured to have a mean of 90.0-110.0% of the claimed label amount of active drug.
  • the FIGURE for Net Related Substance Impurities indicates the percentage of all related substance impurities in the composition (as judged by HPLC peak area). Parenthetically provided is the highest percentage of any single impurity detected. Acceptance of a batch requires that total related substance impurities amount to not more than 3.0%, with no single related substance impurity amounting to more than 0.5%.
  • the Quantifiable R.S. (Related Substances) Impurities FIGURE is the number of distinct detectable HPLC peaks associated with related substance impurities, while the parenthetical FIGURE is for the number of such peaks above the lower limit of quantifiability. For all conditions reported in the table above, no single impurity exceeded the 0.5% acceptance limit.
  • ascorbic acid is a preferred anti-oxidant for maintaining physical and chemical stability of lumateperone tosylate in a tablet formulation blend.

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